Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides

Overview

Journal Science

Specialty Science

Date 2023 Jan 26

PMID 36701435

Authors

Hannah R Bridges

James N Blaza

Zhan Yin

Injae Chung

Michael N Pollak

Judy Hirst

Affiliations

Soon will be listed here.

Abstract

The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.

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